Page 1548 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 85 T-Cell Lymphomas 1375

An example of such an achievement has been the work with now been investigated in the small subset of young MF/SS patients
temozolomide for the treatment of MF/SS. This agent is an oral with HLA-identical siblings or HLA-matched unrelated donors who
imidazotetrazine that has activity in solid tumors, such as brain have poor-prognosis disease and have demonstrated relapse or resis-
tumors and melanoma. It has been determined that mechanisms of tance to IFNs, chemotherapy, and topical therapies. In an early study,
resistance to this agent include expression of high levels of the scav- a single patient treated with cyclophosphamide and total body irra-
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enger protein O -alkylguanine-DNA alkyltransferase (AGT) in diation was reported to achieve CR after aSCT, but relapse occurred
tumor cells. This protein is implicated in the recognition and repair by day 70, necessitating additional therapy. The patient remained in
of alkylator-induced DNA damage introduced by chloroethylnitro- CR and was alive at least 6 years after the transplantation. In light of
sourea (e.g., bis-chloroethylnitrosourea [BCNU]) or methylating this, we and others have begun to explore this approach in patients
agents (temozolomide). The presence of the AGT protein imparts with MF/SS who are young and have matched donors available. We
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resistance by removing toxic lesions formed at the O position of have used as grafts marrow-derived stem cells enriched with peripheral
guanine. Chloroethylnitrosourea cross-links are prevented from blood–derived stem cells or peripheral blood stem cells only. We
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forming by the removal of the chloroethyl lesion from the O position believe that in appropriate patients this approach should continue to
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before rearrangement or by reaction with the intermediate, 1,O - be explored; older patients may benefit from strategies involving the
ethanoguanine, to form a cross-link between DNA and the repair use of RIC regimens that involve less myeloablative preparative regi-
protein. The AGT protein is inactivated in the process. Studies evalu- mens and rely on the effects of the donor marrow to create a GvL
ating AGT levels in patients with brain tumors receiving BCNU effect for disease control. Molina et al reported promising data using
therapy support the role of AGT in resistance to chloroethylating and ASCT for patients with refractory MF/SS. Each of the seven patients
methylating agents. Retrospective and prospective human studies treated had failed a median of seven therapies. Although one patient
have demonstrated a correlation between AGT concentration and received a myeloablative conditioning regimen, five received a RIC
clinical outcome after treatment with BCNU. regimen consisting of fludarabine and melphalan. Each of the patients
Because of the unique sensitivity of MF to topical BCNU, we achieved a clinical remission and resolution of molecular and cytoge-
were interested in exploring levels of AGT in a variety of patients netic evidence of the disease. After a median follow-up of 56 months,
with various stages of MF/SS. Patients with patch or plaque lesions six of the eight patients were alive and free of evidence of lymphoma.
expressed low levels of the AGT protein compared with a number of The other two patients died of transplant-related complications. This
controls with reactive dermatitis, and the level of AGT increased small study provided the impetus to further develop ASCT strategies
correlating with the stage of MF/SS (i.e., patients with malignant for the treatment of advanced CTCL refractory to standard therapies
lymphocytes harvested from peripheral blood or involved lymph at many centers.
nodes had higher levels of AGT than those with patch or plaque A metaanalysis from reports before 2008 of 20 allogeneic and 19
lesions). Given these data, we initiated a prospective trial of temo- ASCTs was reported by Wu et al and includes some of the patients
zolomide in relapsed patients with MF/SS, correlating response to described here. The majority of patients in both groups received
levels of AGT and other known resistance proteins (such as the family myeloablative chemotherapy and total-skin electron beam as prepara-
DNA mismatch repair proteins). tive regimens, with the remainder in the aSCT group receiving RIC
Twenty-six patients with relapsed heavily pretreated stage IB–IVB regimens. In the ASCT group EFS was only 20% at 1 year and 0%
disease were evaluated. The overall RR was 27%, with two complete at 5 years, statistically significantly less the 65% and 60%, respectively,
responders. Median disease-free survival was 4 months. We hypoth- in the aSCT group. Overall survival was also significantly better in
esized that the optimal phenotype that would predict for good the ASCT group, confirming our impressions regarding the limita-
response to therapy would be low levels of AGT combined with tions of ASCT for this disease.
normal levels of several DNA mismatch repair proteins. Interestingly, Since this metaanalysis was published, two larger single-institution
hypermethylation of these DNA repair proteins has been reported to or multiinstitution reports have been published. A European group
result in silencing of the genes and to correlate with lack of the reported the outcomes on 60 patients with MF/SS (36 of 24) who
proteins as assessed by immunohistochemical techniques in patients received either a matched related donor (mRD) or matched unrelated
with MF. This hypermethylation may be more prevalent in more donor (mUD; 45 of 15) ASCT. Survival at 3 years was 54%. A
advanced tumor lesions and suggests that a propensity for mutations multivariate analysis suggested that recipients of mRD ASCT had
may precede clinical progression. It also suggests that patients might better progression-free and overall survival than patients receiving
benefit from treatment with a demethylating agent in combination mUD ASCT transplants, and reduced-intensity transplants had less
with temozolomide. Unfortunately, in the trial above, pretreatment NRM without increased relapse of disease.
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levels of O -methylguanine-DNA methyltransferase (MGMT) and A single-institution trial in the United States reported the outcome
the mismatch repair genes mutL homolog 1 (MLH1)/mutS homolog of 19 patients treated with total-skin electron beam and nonmyeloab-
2 (MSH2) were not predictive of response to temozolomide. lative ASCT in advanced MF/SS. The complete RR was 58%. Relapse
was sometimes treated with reduced immunosuppression or donor
lymphocyte infusions. With a median follow-up of 19 months, the
Role of Stem Cell Transplantation median overall survival had not been reached.

The natural evolution of the use of chemotherapy for this disease has
been to use dose-intensified approaches with hematopoietic reconsti- Other Established Treatments for CTCL
tution with autologous or allogeneic bone marrow or stem cells.
There are few reports in the literature of such treatment programs in Extracorporeal Photopheresis
well-designed prospective clinical trials.
Given the propensity of Sézary cells to be detectable despite a lack An adaptation of the use of psoralen with UVA called extracorporeal
of clinical evidence even in early-stage disease if sophisticated molecu- photopheresis has been described by Edelson et al. Patients ingest
lar techniques are used, it is likely that reinfusion of neoplastic cells 0.6 mg/kg of oral 8-MOP before a treatment. The treatment consists
may occur with autologous bone marrow transplantation. The lack of routine leukapheresis with isolation of the mononuclear cell frac-
of dramatic benefit in low-grade B-cell lymphomas for autologous tion. The cells are then exposed to UVA ex vivo within a special
bone marrow transplantation similarly suggests that this approach chamber inside the pheresis device. In the initial report, Edelson et al
will not benefit patients. We had a very limited experience with documented an 88.5% loss of lymphocyte viability compared with
autologous bone marrow and SCT at our center and abandoned it, control patients treated with the drug alone. Overall, 64% of patients
because of rapid progression of disease, in favor of aSCT. responded to therapy, with the best results in those with generalized
aSCT has been presumed to be curative in small percentages of erythroderma and, presumably, higher circulating Sézary cell levels.
patients with low-grade B-cell lymphomas, and this approach has The mechanism is not thought to be directly cytotoxic, but rather to